DE3534827C2 - - Google Patents

Description

The invention relates to an improved method of manufacture of 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine and its acid addition salts used as medicines are usable.

The 5- (2-chlorobenzyl) -4,5,6,7- produced according to the invention tetrahydrothieno [3,2-c] pyridine has the one given below Formula (I) and is commonly referred to as ticlopidine:

Ticlopidine is a known compound, and its pharmacological effects are in "EUR. MED. CHEM.-CHIMICA THERAPEUTICA ", September-October 1974-9, No. 5, page 487, described. Because of their anti-inflammatory, vasodilatory and inhibitory effects on platelet agglutination are especially ticlopidine and its salts as Medicinal products can be used.

The synthesis of ticlopidine by reaction of 4,5,6,7- Tetrahydrothieno [3,2-c] pyridine of the formula

with 2-chlorobenzyl halide of the formula

where X is Cl, Br or J is already known and for example in "EUR. J. MED. CHEM.-CHIMICA THERAPEUTICA",  September-October 1974-9, No. 5, page 483. At this process the compound of formula (II) and the compound of formula (III) under reflux in ethyl alcohol heated in the presence of potassium carbonate. The procedure did, however the disadvantage that the reaction very quickly up to one considerable extent progresses with formation of many By-products and that the subsequent purification of the reaction mixture is complicated and beyond that reaction the desired product in a yield of only sth Results in 25%. As alternatives to the above method a method is described in the literature (below referred to as reaction path A), in which thieno [3,2-c] pyridine is N-benzylated with 2-chlorobenzyl halide of the formula (III) to the corresponding quaternary ammonium salt, whereupon the reduction with NaBH₄ follows, and a process (below referred to as reaction path B), in which 4,5,6,7-tetrahydrothieno [3,2-c] pyridine of formula (II) with a highly active 2-chlorobenzoic acid halide is reacted to the reduction with LiAlH₄ follows. Have these alternatives however, the disadvantage that they involve more process stages and are cumbersome to implement.

Pathway A

Pathway B

The object of the invention is therefore an improved Process for the preparation of 5- (2-chlorobenzyl) -4,5,6,7- tetrahydrothieno [3,2-c] pyridine and its acid addition salts in high yields and economically create.

After extensive investigations, it has now been found that that in the N-benzylation of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine product obtained on technically simple and can be obtained economically in high yield can if you do the N-benzylation under mild conditions in the presence of a phase transfer catalyst or Performs phase change catalyst.

The object of the invention is thus a process for the preparation of 5- (2-chlorobenzyl) -4,5,6,7- tetrahydrothieno [3,2-c] pyridine of the formula

and its acid addition salts, by reacting a compound of the formula  

with a compound of the formula

where X is Cl, Br or J, which is characterized in that the reaction in the presence a phase transfer catalyst is carried out.

According to a preferred embodiment of the invention, as Phase transfer catalyst or phase change catalyst a quaternary ammonium salt, phosphonium salt or Crown ether used.

The compound of formula (I) can be obtained from the reaction product be isolated in free form or in the form of a salt. The present invention therefore also includes a method for the preparation of the acid addition salts of the compound of formula (I) with inorganic or organic Acids.

In general, phase transfer catalysts work catalysis under mild conditions. If, for example quaternary ammonium or phosphonium salts as catalysts used, the catalysts work as follows: in the reaction system there are two phases, which are immiscible with each other, one of which (in usually an aqueous phase) contains salts that act as bases or nucleophilic agents, and the other (an organic Phase) contains organic substrates with the the above salts react. Because the one containing the salts Phase in the containing the organic substrates Phase does not resolve, no reaction occurs when nothing happens at the interface. Under these circumstances  forms when a quaternary ammonium or Phosphonium salt or halides or a hydrogen sulfate (probably a sulfate) as a phase transition catalyst is added in a solution a lipophilic cation that not only in the aqueous phase, but also in the dissolves organic phase and with the salts in the aqueous Phase comes into contact, being against its own anion the anions present in excess in the aqueous solution exchanges. This anion exchange is carried out by the following equation:

Q⁺X⁻ (aq) + M⁺Nu⁻ (aq) Q⁺Nu⁻ (aq) + M⁺X⁻ (aq),

where Q⁺ for a quaternary cation, X⁻ for an anion, aq for water, M⁺ stand for a metal cation and Nu⁻ for a nucleophile. The desired reaction cannot proceed if only one Anion exchange causes the complete reaction. The Anion, which can act as a nucleophilic agent, now forms together with Q⁺ an ion pair and must be in the organic Phase are transferred. So the conditions are among which a phase transfer catalyst can work, expedient for a second balance, d. H. a phase transfer equilibrium created by the following equation is represented:

Q⁺Nu⁻ (aq) Q⁺Nu⁻ (org).

If a nucleophilic agent or a base (both of the Simplicity represented by Nu) once in the non-polar (organic) phase occurs, runs a Substitution reaction or deprotonation (elimination reaction) starting to form a reaction product. At the nucleophilic substitution reaction optionally forms Q⁺ together with a leaving group an ion pair. If the leaving group is X⁻, an ion pair QX is formed, that enters the equilibrium mentioned above. This Phase transition catalysis cycle is schematically as follows shown:  

The present invention is that these phase transfer or phase transition catalysis to the organic Synthesis is applied. Preferred examples of suitable ones Are phase transition or phase transfer catalysts quaternary ammonium salts, especially trimethylbenzylammonium hydroxide, Tetra-n-butylammonium hydrogen sulfate, trioctylmethylammonium chloride and triethylbenzylammonium chloride; Phosphonium salts, especially tetrabutylphosphonium chloride, and crown ethers, especially 18-crown-6 and dibenzo-18- Crowns-6.

On an industrial scale, the above reaction using a phase transfer catalyst usually in an aqueous organic Two-phase system carried out in the presence of a base. Examples of suitable bases include Sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate. Among these bases is Sodium hydroxide preferred because it is cheap and easy in handling.

In the case of organic solvents, which are the aqueous-organic Building a two-phase system, it can be any Act solvents as long as they don't with water are miscible. Representative examples of suitable ones organic solvents include hydrocarbons, such as benzene, toluene and xylene; Ether, such as isopropyl ether and diethyl ether; and alcohols with 3 or more carbon atoms, such as B. isopropanol and n-butanol. From Position of the economy and solubility of the Reaction product considered are solvents from Benzene type preferred.  

The base largely dissolves in one aqueous phase of the reaction system. The concentration of Base in the aqueous phase is usually about 2.5 to about 5.0 mol, but is not limited to this. water and an organic solvent can be used in any Ratios are used when an aqueous-organic Two-phase system is formed when for example, a benzene type solvent is used the ratio of water to organic Solvent 7: 3 to 3: 7, preferably 5: 5. Since the inventive Procedure carried out under mild conditions wid, the reaction is preferably at about room temperature causes. The response time is usually 24 to 48 hours, although it depends on the reaction temperature and the molar ratio between the compound of the formula (III) and the compound of formula (II) depends. The Amount of the compound of formula (III) based on that the compound of formula (II) is advantageously larger than the equimolar amount, although the reaction so much the faster the full, the higher the amount of Compound of formula (III) is. The catalyst is preferred used in an amount that is about 0.01 to 0.05 Equivalent, based on the compound of formula (II), corresponds, whereby the final compound of formula (I) in good yields is obtained.

When phosphonium salts or crown ethers as phase transfer catalysts or phase transition catalysts the above reaction is even used in an organic one-phase system.

The salts of the compound of formula (I) can according to a known processes are produced.

The invention is illustrated by the following examples explained.  

Example 1

To a solution of 580 mg (3.3 mmol) 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and 640 mg (3.9 mmol) 2-chlorobenzyl chloride in 5.0 ml of benzene was 5 ml of a aqueous 5M NaOH solution and 100 mg of a 40% methanol solution of trimethylbenzylammonium hydroxide added. The Mixture was stirred at room temperature for 40 hours. The reaction mixture was allowed to stand separated an aqueous layer from an organic layer. The organic layer was washed with water and then with a saturated NaCl solution, dried over MgSO₄ and constricted. The residue was purified by silica gel column chromatography cleaned, 650 mg (yield 74.7%) 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine in the form of an oily product, bp 155.0 bis 158.0 ° C (200 Pa). This pyridine was added in 5 ml with hydrogen chloride saturated ethyl alcohol dissolved, and the solution was then concentrated and cooled. The failed hydrochloride was filtered off and dried. The yield was 420 mg (42.4%), mp 190 ° C.

Mass analysis:

(70 eV, M / Z) 265, 263 (M⁺), 125, 110
IR (KBr) 2300 cm ^-1 (wide, hydrochloride)

Example 2

To a solution of 480 mg (2.74 mmol) 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and 528 mg (1.2 times Molar amount) 2-chlorobenzyl chloride in 5 ml of benzene became 5 ml 5M NaOH aqueous solution was added, and then 20 mg trioctylmethylammonium chloride added. The mixture was stirred at room temperature for 40 hours. It was the same subsequent procedure as in Example 1 carried out, whereby 540 mg (yield 74.9%) 5- (2- Chlorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride received, F. 190 ° C.  

Example 3

To a solution of 24.0 g (0.137 mmol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and 26.4 g (0.164 mol) 2-chlorobenzyl chloride in 100 ml of benzene became 150 ml (0.375 mol) of an aqueous 2.5N NaOH solution and 1.0 g (0.003 mol) tetra-n-butylammonium hydrogen sulfate was added. The mixture was stirred at room temperature for 40 hours. The reaction mixture was left standing with an organic layer from an aqueous layer separated. The aqueous layer was washed twice with 100 ml Extracted benzene. The originally separated organic Layer was combined with the extracted benzene layer, and the combined organic layer was washed with water and then washed with a saturated NaCl solution, over K₂CO₃ dried and concentrated. The residue was under distilled under reduced pressure, 28.8 g (yield 80.0%) 5- (2-chlorobenzyl) -4,5,6,7-tetrahydrothieno Obtained [3,2-c] pyridine in the form of an oily product, 155.0 to 158.0 ° C (200 Pa).

The same procedure as in Example 1 gave the hydrochloride, Yield 26.1 g (63.5%).

Claims (2)

1. Process for the preparation of 5- (2-chlorobenzyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine of the formula and its acid addition salts by reacting a compound of the formula with a compound of the formula wherein X is Cl, Br or J, characterized in that the reaction is carried out in the presence of a phase transfer or transition catalyst. 2. The method according to claim 1, characterized in that a quaternary as a phase transfer or transition catalyst Ammonium salt, phosphonium salt or crown ether used becomes.